Enzymatic kinetic resolution of α-hydroxysilanes

Article abstract of DOI:10.1016/j.tetasy.2010.02.030

The enzymatic kinetic resolution of α-hydroxysilanes where the silicon bears a variety of substituents has been explored. Reactions were performed on various α-hydroxysilanes with several commercially available enzymes, solvents, acetylation reagents, and temperatures. The resulting optically active α-hydroxysilanes and their corresponding acetates were obtained in varying yields and ees.

Full text of DOI:10.1016/j.tetasy.2010.02.030

Tetrahedron: Asymmetry 21 (2010) 527–534
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enzymatic kinetic resolution of
a-hydroxysilanes
Ilhwan An a, Edith N. Onyeozili b, Robert E. Maleczka Jr. a,
*
a Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
b Department of Chemistry, Florida A & M University, Tallahassee, FL 32307, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The enzymatic kinetic resolution of
been explored. Reactions were performed on various
able enzymes, solvents, acetylation reagents, and temperatures. The resulting optically active
silanes and their corresponding acetates were obtained in varying yields and ees.
a
-hydroxysilanes where the silicon bears a variety of substituents has
-hydroxysilanes with several commercially avail-
Received 21 January 2010
Accepted 16 February 2010
Available online 13 April 2010
a
a-hydroxy-
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
ment of ( )-1-[(dimethyl)(phenyl)silyl]but-2-yn-1-ol with
a
variety of lipases failed to give any acylated material, the corre-
During our study of the [1,4]-Wittig rearrangement of benzyl-
oxyallylsilanes, we became interested in the synthesis of optically
active
sponding racemic acetate could be partially resolved with A. niger.9
a
-hydroxysilanes (Fig. 1).1 A literature search revealed
2. Results and discussion
asymmetric reduction as the most common approach to such com-
pounds. Specifically, organoborane hydride additions,2 asymmetric
hydrogenations,3 chiral lithium amide reactions,4 and biocatalytic
Owing in part to the limited literature precedent, we decided to
conduct our own study on the enzymatic kinetic resolution of
transformations5 of acylsilanes have afforded
a
variety of
-hydroxysilanes with high levels of enantioselectivity. In many
of these examples, the starting acylsilanes are generated by the
oxidation of racemic -hydroxysilanes, which themselves are pro-
duced via Brook rearrangement-based processes.
a-hydroxysilanes that varied at both the silicon and the organic
a
group flanking the carbinol. Initially, three different enzymes
(Amano AK lipase, Amano PS lipase, and Novozym 435) were
investigated in the kinetic resolution of ( )-1-hydroxyallyltrimeth-
ylsilane rac-1 (Scheme 1). Reactions were run in a sealed tube filled
with substrate, enzyme, vinyl acetate, and 3 Å molecular sieves as a
mixture in pentane, conditions that had previously been employed
during the kinetic resolution of 4-trimethylsilyl-3-butyn-2-ol.11
The results of these screening experiments are summarized in
Table 1. In all cases, (S)-1 reacted faster than (R)-1, as determined
by a Trost-modified Mosher analysis of the unreacted alcohol using
O-methylmandelate.12 The sense of enantioselection was similar to
that observed by Uejima in the resolution of 1-trimethylsilylpropa-
nol with lipase OF 360 and lipoprotein lipase in water-saturated
2,2,4-trimethylpentane, but opposite13 to that seen by Zong in
the kinetic resolution of 1-trimethylsilylethanol with Novozym
435 in C4MImÁPF6 and with CRL in n-hexane.
a
R2
OH
R1
SiR3
R3
Figure 1. Optically active
a
-hydroxysilanes.
As the
were also first made racemic via Brook rearrangements, we also
looked into the enzymatic kinetic resolution of -hydroxysilanes.
a-hydroxysilanes needed for our [1,4]-Wittig studies
a
Enzymatic esterifications or ester hydrolyses would allow us
to avoid the oxidation step and provide ready access to both
These experiments also revealed that for the resolution of rac-1,
Novozym 435 was superior to Amano AK Lipase and Amano PS
lipase in that it afforded better selectivity and shorter reaction
times. As such, the best conditions to emerge out of these first
experiments were to place a sealed tube containing a pentane solu-
tion of the alcohol, 15 mg Novozym 435/mmol rac-1, 1.5 equiv of
vinyl acetate, and 3 Å molecular sieves under a nitrogen atmo-
sphere into an oil bath heated to 38 °C for 33 h. This protocol affor-
ded (S)-acetic acid 1-(trimethylsilyl)-allyl ester (S)-2 in 30%
isolated yield with 98%ee as well as unreacted (R)-1, which was
isolated in 33% yield with 73%ee.
a
-hydroxysilane enantiomers.
We only found a few reports of the enzymatic kinetic resolution
of a limited number of
a-hydroxysilanes. Zong et al. reported
Lipase-catalyzed esterifications of 1-trimethylsilylethanol in both
organic solvents and ionic liquids.6,7 Similarly, Uejima et al.
resolved 1-trimethylsilylpropanol by a hydrolase-promoted ester-
ification.8 In contrast, Guintchin and Bienz found that while treat-
* Corresponding author. Tel.: +1 517 355 9715x124; fax: +1 517 353 1793.
E-mail address: maleczka@chemistry.msu.edu (R.E. Maleczka).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.030

528
I. An et al. / Tetrahedron: Asymmetry 21 (2010) 527–534
OH
OH
OAc
TMS
enzyme
1.5–5.0 equiv vinyl acetate
TMS
TMS
+
3 Å MS, pentane, rt–38 ºC
rac-1
(R)-1
(S)-2
Scheme 1. Enzymatic resolution of ( )-1-hydroxyallyltrimethylsilane 1.
Table 1
Kinetic resolution of rac-1 via Scheme 1
130 mg Amano AK Lipase/mmola
130 mg Amano PS Lipase/mmolb
15 mg Novozym 435/mmolc
Entry
Time (h)
(S)-2c (%ee)
Entry
Time (h)
(S)-2c (%ee)
Entry
Time (h)
(S)-2c (%ee)
1
2
3
4
5
23
96
120
168
192
73
81
80
80
82
1
2
3
4
5
22
24
48
96
169
88
93
94
92
96
1
2
3
4
5
8
13
22
27
33
99
99
99
98
98
a
b
c
Reactions using Amano AK lipase were performed at rt with 5.0 equiv of vinyl acetate in pentane containing 3 Å molecular sieves.
Reactions using Amano PS lipase and Novozym 435 were performed at 38 °C with 1.5 equiv of vinyl acetate in pentane containing 3 Å molecular sieves.
The absolute configuration was assigned by Mosher analysis and chiral GC analysis determined the %ee.
Additional testing showed that increasing the amount of vinyl
group at either the a- or b-vinyl positions (entries 4 and 5) did
acetate (up to 5 equiv) did not improve the selectivity or yield.
Likewise, lowering the Novozym 435 loading to 10 mg/mmol rac-
1 resulted in longer reaction times, lower yields, and little change
in the selectivity.
not acylate at 38 °C, even with increased catalyst loadings. As Nov-
ozym 435 is stable at 70–80 °C, these substrates were exposed to
higher oil bath temperatures.14 At 78 °C and with increased cata-
lyst loading, (E)-1-(trimethylsilyl)-2-buten-1-ol rac-6 did react, al-
beit slowly and with low yield and poor selectivity (entry 4). Other
solvents, including CH2Cl2, THF, benzene, toluene, and t-amyl alco-
hol, were examined, but none of which proved superior to pentane.
On the basis of the above results, we applied the cited proce-
dure to a series of
a-hydroxysilanes. The results from these reac-
tions are summarized in Table 2. Unfortunately, the substrate
scope proved narrow. Exchanging the TMS group for a dimethyl-
phenylsilyl (DMPS) group 3 improved the performance of the reac-
tion (entry 2), whereas the tert-butyldimethylsilyl (TBS) analogue 5
failed to react (entry 3). Substrates with an additional methyl
All other a-hydroxysilanes screened (Fig. 2) failed to react. Even
raising the amount of Novozym 435 to 130 mg/mmol of silane,
upping the equivalents of vinyl acetate, and/or running the reac-
tions at elevated temperatures did not promote acylation.
Table 2
Results of attempted kinetic resolutions of a
-hydroxysilanes with Novozym 435a
Entry
Starting
mg/mmol
Novozym 435
Time
(h)
Temp
(°C)
(R)-Hydroxysilane
(R)-Hydroxysilane
% yield
(S)-Acetate
(S)-Acetate
% yield
a
-hydroxysilane
%eeb
%eeb
OH
1
15
15
33
49
38
38
73b
33% (R)-1
43% (R)-3
>98b
>99b
30% (S)-2
37% (S)-4
TMS
1
OH
2
3
>99b
DMPS
3
OH
15
75
24
85
38
78
n/a
9c
No reaction
n/a
No reaction
TBS
5
OH
d
4
5
11% (R)-6
—
12% (S)-7
Me
TMS
6
OH
TMS
15–75
17
38
n/a
No reaction
n/a
No reaction
Me
8
a
b
c
Reactions were run in a sealed tube containing substrate, Novozym 435, 1.5 equiv vinyl acetate, 3 Å MS, and pentane.
The absolute stereochemistry was assigned by Mosher analysis and either chiral GC or HPLC analysis determined the %ee.
The absolute stereochemistry and %ee were determined by comparing optical rotations of the unreacted alcohol to the literature [
All chromatographic and spectroscopic attempts to resolve the enantiomers and thus determine the %ee failed.
a
]D.10
d

I. An et al. / Tetrahedron: Asymmetry 21 (2010) 527–534
529
Me
OH
Me
OH
OH
OH
TMS
DMPS
Ph
TMS
Ph
DMPS
9
10
11
12
Figure 2. Failed a-hydroxysilanes.
In an attempt to overcome the poor reactivity exhibited by the
methylated substrates (Table 2, entries 4 and 5), we turned to sev-
eral commercially available enzymes that are known to acetylate
secondary alcohols. Thus we tested Amano AK lipase, Amano PS-
D I lipase, Amano PS-C II lipase, and CRL in the kinetic resolution
of 2-methyl-1-(trimethylsilyl)-2-propen-1-ol rac-8 (Scheme 2).
These enzymes afforded some level of reactivity (Table 3), with
Amano PS-D I lipase giving the best results in terms of enantiose-
lectivity. As shown in entry 6, acetate (R)-13 was obtained in 13%
yield with 87%ee, with the alcohol (S)-8 being recovered in 19%
yield with 99%ee. The stereochemical preference was opposite to
that observed during the resolution of rac-1 with Novozym 435.
The low yields of (R)-13 and (S)-8 were partly due to formation
of the acetylated hemiacetal 14 as a main product of the reaction.15
Again, adjustments in the amount of Amano PS-C I lipase and vinyl
acetate and/or solvent did not minimize this acetal formation or
improve the resolution results.
To more directly compare the reactivity of Amano PS-D I lipase
versus Novozym 435, rac-1 was resolved with Amano PS-D I lipase
in the presence of 1.5 equiv of vinyl acetate in toluene at room
temperature (Scheme 3). After ꢀ18 h, rac-1 was completely con-
sumed and acetate (S)-2 was formed in 41% yield with 97%ee. This
indicates that the observed absolute stereochemistry is highly
influenced by relatively small changes to the side chain structure
of the a-hydroxysilane.
While the reactions of rac-1 and rac-8 with Amano PS-D I lipase
afforded different stereochemical outcomes, they were similar in
that both afforded acetal co-products. In the case of rac-1, acetal
enzyme,
acylating
reagent
OH
O
OAc
TMS
OH
OAc
TMS
+
+
TMS
TMS
3 Å MS,
solvent,
rt–40 ºC
Me
(S)-8
Me
Me
rac-8
Me
(R)-13
14
Scheme 2. Enzymatic resolution of rac-8.
Table 3
Kinetic resolution of rac-8a
Entry
Lipase (mg/mmol)
Acylation reagent (equiv)
Solvent
Time (h)
Temp (°C)
(S)-8 %eeb
(S)-8 % yieldc
(R)-13 %eeb
(R)-13 % yieldc
1d
2
3
4
5
Amano PS-C II (144)
Amano AK (72)
CRL (30)
Amano PS-D I (144)
Amano PS-D I (144)
Amano PS-D I (288)
Amano PS-D I (432)
p-ClC6H4OAc (1.5)
Vinyl acetate (16.2)
Vinyl acetate (16.0)
Vinyl acetate (1.5)
Vinyl acetate (1.5)
Vinyl acetate (3.0)
Vinyl acetate (1.5)
CH2Cl2
Neat
209
209
352
115
306
112
140
rt–40
rt
rt
40
10
rt
2
>1e
>48e
56
>99
>99
90
14
81
57
89
2
66
21
9
74
87
87
87
2
13
5
10
5
Cyclohexane
Toluene
Toluene
Toluene
Toluene
6
7
19
22
13
16
rt
a
b
c
Reactions were run in a sealed tube containing the substrate, enzyme, acylation reagent, 3 Å MS, and the solvent.
The absolute configuration was determined by Mosher analysis and chiral GC analysis determined the ee.
Yields were determined by GC using decane as an internal standard.
1.0 equiv triethylamine added.
GC peaks corresponding to (R)- and (S)-8 were partially overlapping.
d
e
Amano PS-D I lipase
(288 mg/mmol substrate),
1.5 equiv vinyl acetate,
OH
O
OAc
TMS
OAc
TMS
+
TMS
3 Å MS, toluene,
rt, ~18 h
2
(S)-
15
rac-1
(41 %, 97 %ee)
OH
C18-SiO2
MeCN, rt
TMS
(R)-1
(>33 %, 64 %ee)
Scheme 3. Enzymatic resolution of rac-1 with Amano PS-D I lipase and hydrolysis of 15.

530
I. An et al. / Tetrahedron: Asymmetry 21 (2010) 527–534
15 was formed.16 Compound 15 could not be purified by silica gel
column chromatography or fractional distillation. However, we
tentatively assigned its structure based on 1H, 13C, HMQC, HMBC,
TOCSY, COSY, and IR analyses. Furthermore, we independently pre-
pared 15 by the reduction of rac-2 with DIBAL followed by acyla-
tion of the resultant hemiacetal. Interestingly, this newly
prepared material had the same impurity profile of 15 made during
the resolution. Treatment of the impure acetal16 with C18 silica gel
in CH3CN at room temperature gave (R)-1 with 64%ee in >33% yield
(Scheme 3).
Michigan State University Mass Spectrometry facility using a
Waters QTOF Ultima mass spectrometer equipped with an electro-
spray ionization (ESI) source. IR spectra were recorded on IR/42
spectrometer by Nicolet at 20 °C. Column chromatography was
performed on SiliaflashÒ P60 by Silicycle. TLC was performed on
aluminum-backed TLC plates by Silicycle. The enantiomeric excess
(ee) values were determined on an Agilent 1100 series HPLC using
a Chiralcel OJ or OD-H columns or on a Varian 3900 GC using a
b-dex tm 325 column.
Although the substrate scope was not as broad as we had hoped,
effective resolutions were realized for 1, 3, and 8. As the advantage
of a resolution is the ability to generate both enantiomers, we next
investigated the procedures for converting the enantioenriched
4.2. Preparation of a-hydroxysilanes
4.2.1. 1-Hydroxyallyltrimethylsilane 1
To a cold (À78 °C), stirred solution of allyl alcohol (5.4 mL,
80.0 mmol) in THF (60 mL) under nitrogen conditions was added
n-BuLi (52.8 mL of a 1.6 M solution in hexane, 84.0 mmol) drop-
wise via a cannula. Upon complete addition of base, the reaction
mixture was stirred for 1 h. Next, TMSCl (10.1 mL, 80.0 mmol
(freshly distilled over CaH2)) was added dropwise via a syringe.
Following this addition, the reaction mixture was stirred for 1.5 h
and then t-BuLi (56.8 mL of a 1.7 M solution in hexane, 97.0 mmol)
was added dropwise via a cannula. After stirring for an additional
1.5 h, the reaction was quenched by the addition of saturated
aqueous NH4Cl and then diluted with ether. The phases were sep-
arated and the aqueous phase was extracted with ether. The com-
bined organics were washed with brine and dried over anhydrous
Na2SO4. After filtration and evaporation, the residue was purified
by silica gel column chromatography using Et2O/hexane (1:9) to
afford 6.4 g of 1 as a colorless oil (61%). 1H NMR (500 MHz, CDCl3)
d 6.00 (ddd, J = 17.2, 10.7, 5.3 Hz, 1H), 5.04 (ddd, J = 17.2, 2.1,
1.6 Hz, 1H), 4.96 (ddd, J = 10.7, 1.9, 1.6 Hz, 1H), 3.99–3.97 (m,
1H), 1.35 (br s, 1H), 0.03 (s, 9H); 13C NMR (125 MHz, CDCl3) d
139.9, 109.4, 69.0, À4.3. The spectral data were consistent with
the literature values.17
acetates into their corresponding chiral
a-hydroxysilanes. Experi-
menting on (S)-4, a variety of reagents were investigated but many
of these led to a decrease in the enantiomeric excess. The most effi-
cient results were achieved with DIBAL (Scheme 4). For example,
when essentially enantiopure (S)-4 (99%ee) was treated with
1.0 equiv of DIBAL in hexane at À78 °C, the corresponding (S)-1-
(dimethylphenylsilyl)-2-propen-1-ol (S)-3 was obtained in 81%
isolated yield with only modest loss of %ee (>99:1 to 96.5:3.5 er).
The same procedure could be applied to (S)-2, albeit with a slightly
greater loss of enantiopurity.
OH
OAc
DMPS
DMPS
(S)-4 (99 %ee)
(S)-3 (81%, 93 %ee)
1.0 equiv DIBAL
or
or
hexane,
–78 ºC, 3 h
OH
OAc
TMS
TMS
(S)-2 (98 %ee)
4.2.2. 1-(Dimethylphenylsilyl)-2-propen-1-ol 3
The reaction was carried out on allyl alcohol (2.7 mL,
40.0 mmol) as described in the preparation of 1 (Section 4.2.1) ex-
cept that chlorodimethylphenylsilane (7.0 mL, 42.0 mmol) was
used as the silylating agent and that following its addition, the
reaction mixture was stirred for 1.25 h and that after the t-BuLi
addition, it was stirred for an additional 2.0 h. This modified proto-
col afforded 3.2 g of 3 as a pale yellow oil (42%). 1H NMR (500 MHz,
CDCl3) d 7.5–7.54 (m, 2H), 7.39–7.33 (m, 3H), 5.98 (ddd, J = 17.2,
10.7, 5.3 Hz, 1H), 5.07–5.03 (m, 1H), 5.00–4.97 (m, 1H), 4.21
(ddd, J = 5.3, 2.1, 2.1 Hz, 1H), 1.28 (br s, 1H), 0.34 (s, 1H), 0.32 (s,
1H); 13C NMR (125 MHz, CDCl3) d 139.3, 136.0, 134.2, 129.5,
127.8, 110.0, 68.4, À5.8, À6.1; IR (neat) 3420 cmÀ1; HRMS (EI)
(m/z) calcd for C11H16OSi [M]+ 192.0970, found 192.0963. The spec-
troscopic data were consistent with the literature values.18
(S)-1 (78%, 89 %ee)
Scheme 4. DIBAL reduction of optically active acetates.
3. Conclusions
In conclusion, we have investigated the scope and limitation of
enzymatic kinetic resolution of -hydroxysilanes in combination
a
with different enzymes, solvents, temperatures, and acetylation re-
agents. The reactions are sensitive to the structures of both the silyl
group and the organic side chain. ( )-1-Hydroxyallyltrimethylsi-
lane and its DMPS analogue respond well to Novozym 435. ( )-2-
Methyl-1-(trimethylsilyl)-2-propen-1-ol can be resolved with
Amano PS-D I lipase. The addition of the a-methyl group reverses
the absolute stereochemistry of the esterification. The optically ac-
tive acetates so formed can be converted to their enantioenriched
-hydroxysilanes with DIBAL. Unfortunately, the addition of sub-
stituents to the b-position of ( )-1-hydroxyallyltrimethylsilane
affords substrates that do not resolve under the conditions
described herein. We are currently directing efforts to overcome
this limitation.
4.2.3. 1-[(1,1-Dimethylethyl)dimethylsilyl]-2-propen-1-ol 519
To
a
cold (À78 °C), stirred solution of (1,1-dimethyl-
a
ethyl)dimethyl(2-propen-1-yloxy)silane (8.3 g, 48.6 mmol) in THF
(200 mL) under nitrogen condition were added tetramethylethyl-
enediamine (13.1 mL, 88.0 mmol) and then sec-BuLi (59.7 mL,
1.4 M in cyclohexane, 84.0 mmol) dropwise. The reaction mixture
was warmed up to À40 °C and then stirred for 3.5 h. It was re-
cooled to À78 °C and the reaction was quenched by the addition
of AcOH (17.9 mL, 314.0 mmol) in THF (53 mL). The reaction mix-
ture was warmed to room temperature and extracted with ether.
Combined organic phases were washed with water and brine and
dried over MgSO4. The residue was purified over silica gel column
chromatography using EtOAc/hexane (1:30) to afford 0.7 g of 5 as a
colorless oil (9%). 1H NMR (500 MHz, CDCl3) d 6.05 (ddd, J = 17.2,
10.7, 5.3 Hz, 1H), 5.06 (ddd, J = 17.2, 2.1, 1.6 Hz, 1H), 4.97 (ddd,
4. Experimental
4.1. General
The NMR spectra were recorded on Varian UnityPlus-500 spec-
trometer. Optical rotations were measured on a Perkin–Elmer 341
polarimeter. High-resolution mass spectra were acquired at the

I. An et al. / Tetrahedron: Asymmetry 21 (2010) 527–534
531
J = 10.7, 3.5, 1.6 Hz, 1H), 4.16 (ddd, J = 5.3, 2.1, 2.1 Hz, 1H), 0.94 (s,
9H), 0.11 (s, 3H), À0.06 (s, 3H); 13C NMR (125 MHz, CDCl3) d 140.7,
109.4, 67.6, 26.0, 17.0, À7.6, À9.2. The spectroscopic data were
consistent with the literature values.20
3.47 (m, 1H), 1.55–1.47 (m, 3H), 1.30–1.18 (m, 6H), 0.85 (t,
J = 7.04 Hz, 3H), 0.32 (s, 3H), 0.31 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 136.8, 134.1, 129.2, 127.9, 65.5, 33.4, 31.7, 26.5, 22.6,
14.0, À5.3, À5.7. The spectroscopic data were consistent with the
literature values.25
4.2.4. (2E)-1-(Trimethylsilyl)-2-buten-1-ol 6
The reaction was carried out as described for the preparation of
1 (Section 4.2.1) except that (2E)-2-buten-1-ol (5.7 mL, 67.5 mmol)
served as the alcohol and reaction times following the addition of
TMSCl and t-BuLi addition were 2.5 h and 2.0 h, respectively. This
modified protocol afforded 5.3 g of 6 as a pale yellow oil (54%).
1H NMR (500 MHz, CDCl3) d 5.61–5.42 (m, 2H), 3.86 (doublet of
pentets, J = 6.8, 1.4 Hz, 1H), 1.68 (dt, J = 6.3, 1.4 Hz, 3H), 1.27 (br
s, 1H), 0.01 (s, 9H); 13C NMR (125 MHz, CDCl3) d 132.4, 122.2,
68.4, 17.8, À4.2; IR (neat) 3416 cmÀ1; HRMS (EI) (m/z) calcd for
C7H16OSi [M]+ 144.0970, found 144.0970. The spectroscopic data
were consistent with the literature values.21
4.2.8. a
-(Trimethylsilyl)-benzenemethanol 1126
At first, DMSO (0.7 mL, 11.0 mmol) was added dropwise by syr-
inge to a stirred cold (À78 °C) solution of oxalyl chloride (0.8 mL,
10.5 mmol) in anhydrous ether under nitrogen. The reaction mix-
ture was warmed to À35 °C and then stirred for 1 h. It was then
cooled back down to À78 °C and (trimethylsilyl)methanol
(1.2 mL, 10.0 mmol) was added dropwise. The reaction mixture
was warmed to À35 °C and stirred for 2 h. It was again cooled to
À78 °C and triethylamine (6.9 mL, 50.0 mmol (freshly distilled over
CaH2)) was added dropwise. The reaction mixture was stirred for
2 h at the same temperature and then warmed to 0 °C and stirred
for 4 h. It was recooled to À78 °C and bromophenylmagnesium
(9.0 mL, 50.0 mmol) was added dropwise. After the reaction mix-
ture was stirred for 2 h at À78 °C, water (20 mL) and ether
(90 mL) were added and the mixture was allowed to warm to room
temperature. The phases were separated and the aqueous phase
was extracted with ether. Combined organics were washed with
brine and dried over anhydrous MgSO4. After filtration and evapo-
ration, the residue was purified over silica gel column chromatog-
raphy using Et2O/hexane (1:9) to afford 0.8 g of 11 as a colorless oil
(47%). 1H NMR (500 MHz, CDCl3) d 7.30–7.26 (m, 2H), 7.18–7.13
(m, 3H), 4.51 (s, 1H), 1.65 (br s, 1H), 0.00 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 144.2, 128.1, 125.8, 124.9, 70.6, À4.2. The spec-
troscopic data were consistent with the literature values.27
4.2.5. 2-Methyl-1-(trimethylsilyl)-2-propen-1-ol 8
The reaction was carried out as described for the preparation of
1 (Section 4.2.1) except that 2-methyl-2-propen-1-ol (6.6 mL,
79.0 mmol) served as the alcohol and that following the addition
of TMSCl, the reaction mixture was stirred for 1.0 h, before t-BuLi
(55.6 mL 1.7 M in hexane, 95.0 mmol) was added dropwise via a
cannula. After stirring for an additional 3 h at À33 °C, the cold bath
was removed and a solution of acetic acid (5.4 mL, 95.0 mmol) in
THF (5 mL) was added. After the reaction mixture was stirred for
30 min, saturated aqueous NaHCO3 (60 mL) and pentane
(100 mL) were added. Workup and chromatography as previously
described afforded 9.1 g of 8 as a colorless oil (81%). 1H NMR
(500 MHz, CDCl3) d 4.77 (oct, J = 0.8 Hz, 1H), 4.74 (dq, J = 3.0,
1.5 Hz, 1H), 3.86 (s, 1H), 1.69 (t, J = 0.7 Hz, 3H), 1.29 (br d,
J = 2.60, 1H), 0.06 (s, 9H); 13C NMR (125 MHz, CDCl3) d 148.3,
106.3, 71.6, 20.7, À3.4. The spectroscopic data were consistent
with the literature values.22
4.2.9. a-(Dimethylphenylsilyl)-benzenemethanol 12
The reaction was carried out as described for the preparation of
10 (Section 4.2.7) except that PhMe2SiLi was formed over 36 h and
benzaldehyde (0.4 mL, 4.3 mmol) served as the aldehyde. This
modified protocol afforded 0.4 g of 12 as a colorless oil (40%). 1H
NMR (500 MHz, CDCl3) d 7.47–7.45 (m, 2H), 7.39–7.31 (m, 3H),
7.25–7.21 (m, 2H), 7.16–7.12 (m, 1H), 7.08–7.05 (m, 2H), 4.69 (s,
1H), 1.64 (br s, 1H), 0.28 (s, 3H), 0.25 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 143.5, 135.9, 134.3, 129.4, 128.0, 127.8, 125.9, 125.1,
70.0, À5.4, À6.3. The spectroscopic data were consistent with the
literature values.23
4.2.6. (2E)-1-(Trimethylsilyl)-2-hexene-1-ol 9
The reaction was carried out as described for the preparation of
1 (Section 4.2.1) except that (2E)-2-hexen-1-ol (2.3 mL, 20.0 mmol)
served as the alcohol, sec-BuLi (17.1 mL 1.4 M in cyclohexane,
24.0 mmol) was used in the place of t-BuLi, and reaction times fol-
lowing the addition of TMSCl and s-BuLi addition were 2.5 h and
2.0 h, respectively. This modified protocol afforded 1.9 g of 9 as a
pale yellow oil (57%). 1H NMR (500 MHz, CDCl3) d 5.57 (dddd,
J = 1.3, 1.3, 6.6, 15.4 Hz, 1H), 5.47 (dddd, J = 1.5, 6.8, 6.8, 15.1 Hz,
1H), 3.89–3.87 (m, 1H), 2.02–1.97 (m, 2H), 1.37 (sext, J = 7.3 Hz,
2H), 1.27 (br s, 1H), 0.87 (t, J = 7.4 Hz, 3H), 0.01 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 131.4, 127.5, 68.4, 34.6, 22.8, 13.6, À4.2. The
spectroscopic data were consistent with the literature values.23
4.3. Acylation of a-hydroxysilanes
4.3.1. Acetic acid 1-(trimethylsilyl)-allyl ester 2
To a solution of 1-hydroxyallyltrimethylsilane (0.6 g, 4.81 mmol)
and pyridine (0.3 mL, 4.8 mmol) was added acetic anhydride
(0.4 mL, 4.8 mmol). The reaction mixture was stirred at room
temperature overnight. It was diluted with Et2O, and then sequen-
tially extracted with 1 M HCl, saturated aqueous NaHCO3, and brine.
The ethereal layer was dried over MgSO4, filtered, and evaporated to
afford0.5 g of 2as a pale yellowoil(67%). 1HNMR(500 MHz, CDCl3)d
5.83 (ddd, J = 17.0, 10.9, 5.8 Hz, 1H), 5.17 (ddd, J = 5.8, 1.8, 1.8 Hz,
1H), 4.98 (ddd, J = 9.3, 1.7, 1.7 Hz, 1H), 4.96 (m, 1H), 2.07 (s, 3H),
0.07 (s, 9H); 13C NMR (125 MHz, CDCl3) d 170.7, 134.9, 111.3, 70.6,
20.9, À4.0; IR 1734 (s) cmÀ1; HRMS (EI) (m/z) calcd for C8H16O2Si
[M]+ 172.0920, found 172.0923. The spectroscopic data were consis-
tent with the literature values.28
4.2.7. 1-(Dimethylphenylsilyl)-1-hexanol 1024
Chlorodimethylphenylsilane (9.7 mL, 57.9 mmol) was added to
a rapidly stirring mixture of lithium wire (0.9 g, 135.0 mmol (fine
cut)) in THF (60 mL) at room temperature. The reaction mixture
was stirred for 31 h at room temperature, giving a deep red solu-
tion of PhMe2SiLi. This PhMe2SiLi solution was then added drop-
wise via a cannula to a cold (À78 °C) stirred solution of hexanal
(0.7 mL, 5.8 mmol) in THF (6 mL). The reaction mixture was stirred
for 30 min at the same temperature before the reaction being
quenched by the addition of saturated aqueous NH4Cl solution.
The reaction mixture was extracted twice with ether. The com-
bined organics were washed with water and brine and then dried
over MgSO4. After filtration and evaporation, the residue was puri-
fied over silica gel column chromatography using Et2O/hexane
(1:9) to afford 0.6 g of 10 as a pale yellow oil (44%). 1H NMR
(500 MHz, CDCl3) d 7.55–7.53 (m, 2H), 7.37–7.34 (m, 3H), 3.50–
4.3.2. Acetic acid 1-(dimethylphenylsilyl)-prop-2-enyl ester 4
Applying the acylation procedure described for the preparation
of 2 to 1-(dimethylphenylsilyl)-2-propen-1-ol (0.4 g, 2.6 mmol)
afforded 0.5 g of 4 as a pale yellow oil (85%). 1H NMR (500 MHz,
CDCl3) d 7.53–7.50 (m, 2H), 7.40–7.33 (m, 3H), 5.82–5.75 (m,
1H), 5.39 (ddd, J = 5.7, 1.9, 1.9 Hz, 1H), 4.98 (ddd, J = 4.6, 1.6,

532
I. An et al. / Tetrahedron: Asymmetry 21 (2010) 527–534
1.6 Hz, 1H), 4.95–4.94 (m, 1H), 2.04 (s, 3H), 0.34 (d, J = 0.8 Hz, 6H);
13C NMR (125 MHz, CDCl3) d 170.7, 135.5, 134.9, 134.3, 129.8,
128.1, 112.1, 70.2, 21.2, À5.3, À5.4; IR (neat) 1740 cmÀ1; HRMS
(EI) (m/z) calcd for C13H18O2Si [M]+ 234.1076, found 234.1078.
The spectroscopic data were consistent with the literature
values.18a
4.4.4. PS-D I resolution of rac-3 (Table 3, entry 6)
To a sealed tube containing a solution of racemic 2-methyl-1-
(trimethylsilyl)-2-propen-1-ol (144 mg, 1.0 mmol) and activated
3 Å molecular sieves in toluene (1 mL) were added PS-D
I
(288 mg) and vinyl acetate (0.3 mL, 3.0 mmol). The tube was
purged with N2 and sealed. The tube was purged with N2, sealed,
and the reaction mixture was stirred with the reaction progress
being monitored by GC. After ꢀ44% of the starting material was
consumed, the reaction mixture was filtered through a pad of Cel-
ite. Analysis of the filtrate by GC (VF-1ms column) using decane as
an internal standard indicated that the optically active acetate (R)-
13 was formed in 13% yield (87%ee) and the unreacted optically ac-
tive alcohol (S)-8 was formed in 19% yield (>99%ee).
4.3.3. Acetic acid 1-(trimethylsilyl)-but-2(E)-enyl ester 7
Applying the acylation procedure described for the preparation
of 2 to (2E)-1-(trimethylsilyl)-2-buten-1-ol (0.7 g, 5.0 mmol) affor-
ded 0.5 g of 7 as a substrate (colorless oil, 61%). 1H NMR (500 MHz,
CDCl3) d 5.49–5.39 (m, 2H), 5.09–5.06 (m, 1H), 2.02 (s, 3H), 1.65
(dd, J = 4.8, 1.1 Hz, 3H), 0.00 (s, 9H); 13C NMR (125 MHz, CDCl3) d
170.7, 127.5, 124.5, 70.3, 21.0, 17.8, À3.9; IR (neat) 1742 cmÀ1
;
HRMS (EI) (m/z) calcd for C9H18O2Si [M]+ 186.1076, found
186.1079. The spectroscopic data were consistent with the litera-
ture values.22
4.4.5. Kinetic resolution of rac-1 using amino PS-D I lipase
(Scheme 3)
At first, PS-D I (288 mg) and vinyl acetate (0.14 mL, 1.5 mmol)
were added to a tube containing a mixture of racemic 1-hydroxy-
allyltrimethylsilane (0.13 g, 1.0 mmol) and activated 3 Å molecular
sieves in toluene (1 mL). The tube was purged with N2, sealed, and
the reaction mixture was stirred with the reaction progress being
monitored by GC. After ꢀ100% of the starting material was con-
sumed, the reaction mixture was filtered through a pad of Celite
503. Analysis of the filtrate by GC (VF-1ms column) using decane
as an internal standard indicated that the optically active (S)-2
was formed in 41% yield (97%ee) as well as presumed 1516 and
an impurity.
4.3.4. Acetic acid 2-methyl-1-(trimethylsilyl)-allyl ester 13
Applying the acylation procedure described for the preparation
of 2 to 2-methyl-1-(trimethylsilyl)-2-propen-1-ol (0.1 g, 0.7 mmol)
afforded 0.07 g of 13 as a pale yellow oil (55%). 1H NMR (500 MHz,
CDCl3) d 5.01 (s, 1H), 4.72–4.71 (m, 1H), 4.69–4.67 (m, 1H), 2.06 (s,
3H), 1.71–1.69 (m, 3H), 0.06 (s, 9H); 13C NMR (125 MHz, CDCl3) d
170.7, 143.3, 107.9, 72.7, 21.0, 20.7, À3.3; IR (neat) 1770 cmÀ1
;
HRMS (EI) (m/z) calcd for C9H18O2Si [M]+ 186.1076, found
186.1078. The spectroscopic data were consistent with the litera-
ture values.29
4.5. Preparation and hydrolysis of acetal 15 by C18 silica gel
(Scheme 3)
4.4. Kinetic resolution of a-hydroxysilanes (Table 2)
4.4.1. Resolution of ( )-1-hydroxyallyltrimethylsilane 1 (Table 2,
entry 1)
At first, PS-D I (2.88 g) and vinyl acetate (1.4 mL, 15.0 mmol)
were added to a sealed tube containing a mixture of racemic 1-
hydroxyallyltrimethylsilane (1.39 g, 10.6 mmol) and activated 3 Å
molecular sieves in toluene (10 mL). The sealed tube was purged
with N2 and the mixture was stirred at room temperature and
monitored by GC. The tube was purged with N2, sealed, and the
reaction mixture was stirred with the reaction progress being
monitored by GC. After ꢀ100% of the starting material had been
consumed, the reaction mixture was filtered through a pad of Cel-
ite 503, concentrated, and subjected to silica gel column chroma-
tography using Et2O/hexane (1:9), which afforded a mixture of
(S)-2, presumed acetal 1516, and an unidentified impurity. Com-
pound (S)-2 was removed by rotary evaporation, leaving 117 mg
acetal 15 and the impurity. Acetal 15 and the impurity (48 mg)
were dissolved in CH3CN (2 mL) to which C18 silica gel (500 mg)
was added. The mixture was stirred at room temperature for
20 min, filtered, concentrated, and purified by silica gel column
chromatography using Et2O/hexane (1:9) to afford 10 mg of (R)-1
as a colorless oil (>33%, 64%ee).
Novozym 435 (30 mg; 15 mg/mmol (rac)-alcohol) and vinyl
acetate (0.3 mL, 3.0 mmol) were added to a tube containing a mix-
ture of ( )-1-hydroxyallyltrimethylsilane 1 (261 mg, 2.0 mmol)
and activated 3 Å molecular sieves in pentane (1.0 mL). The tube
was purged with N2 and sealed. The sealed tube was placed in a
38 °C oil bath and the reaction mixture was stirred with the reac-
tion progress being monitored by GC. After ꢀ50% of the starting
material was consumed, the reaction mixture was filtered through
a pad of Celite 503, concentrated, and purified by silica gel column
chromatography using Et2O/hexane (1:9) to afford optically active
acetate (S)-2 (104 mg, 30%, [
and unreacted optically active alcohol (R)-1 (86 mg, 33%,
D = À7.1 (c 1.05, CHCl3, 73%ee)).
a]
D = À17.5 (c 1.03, CHCl3, >98%ee))
[a]
4.4.2. Resolution of ( )-1-(dimethylphenylsilyl)-2-propen-1-ol 3
(Table 2, entry 2)
Applying the kinetic resolution procedure described in Sec-
tion 4.4.1 to ( )-1-(dimethylphenylsilyl)-2-propen-1-ol
(385 mg, 2.0 mmol) afforded after ꢀ49% conversion optically active
acetate (S)-4 (174 mg, 37%, [
3
4.6. Reductive cleavage of optically active acetates
a]
D = À10.1 (c 1.26, CHCl3, 99%ee)) and
4.6.1. Reduction of (S)-2 (Scheme 4)
unreacted optically active alcohol (R)-3 (167 mg, 43%, [
a]
D = À8.8
A solution of compound (S)-2 (138 mg, 0.8 mmol, >98%ee) in
hexane (3 mL) was cooled to À78 °C. To that cold solution, DIBAL
(0.8 mL of a 1.0 M solution in hexane, 0.8 mmol) was added drop-
wise. The reaction mixture was then stirred at the same tempera-
ture for 2.5 h. The cold bath was removed, the reaction was
quenched with saturated aqueous Rochelle Salt (1.5 mL), and the
reaction mixture was diluted with ether. The phases were sepa-
rated, the aqueous phase was extracted with ether, and the com-
bined organics were dried over Na2SO4. After filtration and
evaporation, the residual oil was purified by silica gel column chro-
matography using Et2O/hexane (1:9) to afford 82 mg of (S)-1 (78%;
(c 1.04, CHCl3, 99%ee)).30
4.4.3. Resolution of ( )-(2E)-1-(trimethylsilyl)-2-buten-1-ol 6
(Table 2, entry 4)
Applying the kinetic resolution procedure described in Sec-
tion 4.4.1 to ( )-(2E)-1-(trimethylsilyl)-2-buten-1-ol 6 (300 mg,
2.1 mmol) at 78 °C afforded after ꢀ46% conversion acetate 7
(46 mg, 12%, (all chromatographic and spectroscopic attempts to
resolve the enantiomers and thus determine the %ee failed)) and
unreacted optically active alcohol (R)-6 (34 mg, 11%, [
(c 1.12, CHCl3, 9%ee)).
a]D = +4.1
[a]
D = +8.3 (c 1.21, CHCl3, 89%ee31).

I. An et al. / Tetrahedron: Asymmetry 21 (2010) 527–534
533
4.6.2. Reduction of (S)-4 (Scheme 4)
The organic layer was dried over MgSO4, filtered, and evaporated to
afford the crude Mosher ester, which was immediately analyzed by
1H NMR (300 MHz, CDCl3, pertinent peaks only) d 5.75–5.62 (m,
1H), À0.04 (d, J = 0.8 Hz, 9H).
Applying the conditions described above (Section 4.6.1) to (S)-4
(73 mg, 0.3 mmol) in hexane (1.5 mL) using 1.1 equiv of DIBAL
(0.3 mL of a 1.0 M solution in hexane, 0.3 mmol) afforded 49 mg
of (S)-3 (81%; [
a]
D = +8.2 (c 1.12, CHCl3, 93%ee).
Applying the aforementioned procedure to (R)-1-hydroxyallyl-
trimethylsilane (46 mg, 0.35 mmol) and (S)-(+)-a-methoxyphen-
4.7. Chiral GC and HPLC analyses
ylacetic acid (47 mg, 0.28 mmol) afforded the crude Mosher
ester, which was immediately analyzed by 1H NMR (300 MHz,
CDCl3, pertinent peaks only) d 5.89–5.74 (m, 1H), À0.22 (d,
J = 0.7 Hz, 9H).
4.7.1. 1-Hydroxyallyltrimethylsilane 1
GC Column: b-dex tm 325 (30 m  0.25 mm  0.25
lm film
thickness). Program: 30–150 °C, at 5 °C/min, hold at 150 °C for
2 min. tr-(R) enantiomer (min) = 10.0 min, tr-(S) enantiomer
(min) = 9.8 min.
O
MPA
Ph
Si
Me
H
4.7.2. Acetic acid 1-(trimethylsilyl)-allyl ester 2
H
GC Column: b-dex tm 325 (30 m  0.25 mm  0.25
lm film
–0.086
+0.192
thickness). Program: 30–150 °C, at 5 °C/min, hold at 150 °C for
2 min. Results: tr-(R) enantiomer (min) = 12.9 min, tr-(S) enantio-
mer (min) = 13.0 min.
δ
(R)-MPA-(R)-ester – δ(S)-MPA-(R)-ester
4.8.2. (R)-1-(Dimethylphenylsilyl)-2-propen-1-ol Mosher esters
Applying the Section 4.8.1 procedure to (R)-1-(dimethylphenyl-
4.7.3. 1-(Dimethylphenylsilyl)-2-propen-1-ol 3
HPLC column: Chiralcel OJ. Eluent: IPA/hexane (90:10),
0.18 mL/min. Results: tr-(R) enantiomer (min) = 23.6 min, tr-(S)
enantiomer (min) = 30.9 min.
silyl)-2-propen-1-ol (72 mg, 0.37 mmol) and (R)-(À)-
a-methoxy-
phenylacetic acid (50 mg, 0.30 mmol) (7 h reaction time) afforded
the crude Mosher ester, which was immediately analyzed by 1H
NMR (300 MHz, CDCl3, pertinent peaks only) d 5.71–5.58 (m, 1H),
À0.27 (d, J = 2.8 Hz, 6H).
4.7.4. Acetic acid 1-(dimethylphenylsilyl)-prop-2-enyl ester 4
HPLC column: Chiralcel OJ. Eluent: IPA/hexane (90:10),
0.18 mL/min. Results: tr-(R) enantiomer (min) = 31.2 min, tr-(S)
enantiomer (min) = 35.4 min.
Applying the Section 4.8.1 procedure to (R)-1-(dimethylphenyl-
silyl)-2-propen-1-ol (72 mg, 0.37 mmol) and (S)-(+)-a-methoxy-
phenylacetic acid (50 mg, 0.30 mmol) (7 h reaction time) afforded
the crude Mosher ester, which was immediately analyzed by 1H
NMR (300 MHz, CDCl3, pertinent peaks only) d 5.79–5.66 (m, 1H),
À0.08 (d, J = 4.3 Hz, 6H).
4.7.5. (2E)-1-(Trimethylsilyl)-2-buten-1-ol 6
GC Column: b-dex tm 325 (30 m  0.25 mm  0.25
lm film
thickness). Program: 30–150 °C, at 1 °C/min, Results: tr-(R) enan-
tiomer (min) = 29.2 min, tr-(S) enantiomer (min) = 29.9 min.
O
MPA
Me
Me
4.7.6. 2-Methyl-1-(trimethylsilyl)-2-propen-1-ol 8
Si
GC Column: b-dex tm 325 (30 m  0.25 mm  0.25
lm film
thickness). Program: 45 °C for 20 min, 45–150 °C, at 2 °C/min. Re-
sults: tr-(R) enantiomer (min) = 27.7 min, tr-(S) enantiomer
(min) = 28.1 min.
H
H
–0.159
+0.183
δ
(R)-MPA-(R)-ester – δ(R)-MPA-(S)-ester
4.7.7. Acetic acid 2-methyl-1-(trimethylsilyl)-allyl ester 13
GC Column: b-dex tm 325 (30 m  0.25 mm  0.25
lm film
4.8.3. (S)-2-Methyl-1-(trimethylsilyl)-2-propen-1-ol 8 Mosher
esters
thickness). Program: 45 °C for 20 min, 45–150 °C, at 2 °C/min. Re-
sults: tr-(R) enantiomer (min) = 36.0 min, tr-(S) enantiomer
(min) = 35.8 min.
Applying the Section 4.8.1 procedure to (S)-2-methyl-1-(tri-
methylsilyl)-2-propen-1-ol (30 mg, 0.21 mmol) and (R)-(À)-
a-
methoxyphenylacetic acid (28 mg, 0.17 mmol) (7 h reaction time)
afforded the crude Mosher ester, which was immediately analyzed
by 1H NMR (300 MHz, CDCl3, pertinent peaks only) d 1.67 (s, 3H),
À0.19 (s, 9H).
4.8. Mosher’s ester analyses12
O
MPA
Me
Me
Applying the Section 4.8.1 procedure to (rac)-2-methyl-1-(tri-
methylsilyl)-2-propen-1-ol (100 mg, 0.69 mmol) and (R)-(À)-
a-
Si
methoxyphenylacetic acid (94 mg, 0.56 mmol) (7 h reaction time)
afforded the crude Mosher ester, which was immediately analyzed
by 1H NMR (300 MHz, CDCl3, pertinent peaks only) d 1.67 (s, 3H),
1.51 (s, 3H), 0.00 (s, 9H), À0.19 (s, 9H).
H
H
–0.118
+0.189
δ
(R)-MPA-(R)-ester – δ(S)-MPA-(R)-ester
4.9. Synthesis of acetal 1532
4.8.1. (R)-1-Hydroxyallyltrimethylsilane Mosher esters
To solution of (R)-1-hydroxyallyltrimethylsilane (46 mg,
0.35 mmol), -methoxyphenylacetic acid (47 mg,
0.28 mmol), and DCC (65 mg, 0.31 mmol) in CH2Cl2 (3.5 mL) under
nitrogen was added DMAP (4 mg, 0.032 mmol) in a single portion.
The reaction mixture was stirred at room temperate for 4 h. The
precipitate formed was removed by filtration and the filtrate was
washed with cold 1 M HCl, saturated aqueous NaHCO3, and brine.
a
To a cold (À78 °C), stirred solution of ( )-1-trimethylsilylallyl
acetate 2 (155 mg, 0.9 mmol) in CH2Cl2 (5 mL) under nitrogen con-
ditions was added DIBAL (1.8 mL of a 1.0 M solution in hexane,
1.8 mmol) dropwise. The resulting reaction mixture was then stir-
red for 45 min, after which pyridine (0.2 mL, 2.7 mmol), a solution
of DMAP (221 mg, 1.8 mmol) in CH2Cl2 (2 mL), and acetic anhy-
(R)-(À)-
a

534
I. An et al. / Tetrahedron: Asymmetry 21 (2010) 527–534
14. (a) Arroyo, M.; Sinisterra, J. V. J. Org. Chem. 1994, 59, 4410–4417; (b) Persson, B.
A.; Larsson, A. L. E.; Le Ray, M.; Bäckvall, J. E. J. Am. Chem. Soc. 1999, 121, 1645–
1650.
15. (a) Isaksson, D.; Lindmark-Henriksson, M.; Manoranjan, T.; Sjödin, K.; Högberg,
H. E. J. Mol. Catal. B: Enzym. 2004, 31, 31–37; (b) Högberg, H. E.; Lindmark, M.;
Isaksson, D.; Sjödin, K.; Franssen, M. C. R.; Jongejan, H.; Wijnberg, J. B. P. A.; de
Groot, A. Tetrahedron Lett. 2000, 41, 3193–3196.
dride (0.5 mL, 5.4 mmol) were added dropwise. After stirring for an
additional 29 h, the reaction mixture was warmed to 0 °C and stir-
red for 0.5 h. The reaction was quenched by the addition of satu-
rated aqueous NH4Cl and sodium potassium tartrate at 0 °C. The
resulting solution was warmed to room temperature, stirred for
an additional 0.5 h, and then diluted with CH2Cl2. The phases were
separated and the aqueous phase was extracted with CH2Cl2. The
combined organics were washed with ice-cooled 1 M sodium
bisulfate, saturated aqueous NaHCO3, and brine to afford 61 mg
(<31%) of presumed acetal 15.16
16. Acetal 15 proved difficult to purify. GC (VF-1ms column) of the
chromatographed material gave three peaks at 2.6, 6.2, and 6.4 min with a
ratio of (9:32:59). This mixture provided the following data: major (GC peak at
6.4 min) 1H NMR (500 MHz, CDCl3) d 5.96 (q, J = 5.3 Hz, 1H), 5.92–5.87 (m,
overlapped), 5.07–4.96 (m, 2H), 3.83–3.80 (m, 1H), 2.00 (s, 3H), 1.38 (d,
J = 5.3 Hz, 3H), 0.03 (s, overlapped); 13C NMR (125 MHz, CDCl3) d 170.6, 137.8,
110.7, 98.1, 78.3, 21.4, 21.1, À4.2; IR (neat) 1740 cmÀ1; minor (GC peak at
6.2 min) 1H NMR (500 MHz, CDCl3) d 5.92–5.87 (m, overlapped), 4.93–4.88 (m,
2H), 3.93–3.89 (m, 1H), 2.06 (s, 3H), 1.40 (d, J = 5.2 Hz, 3H), 0.04 (s,
overlapped); 13C NMR (125 MHz, CDCl3) d 170.8, 136.2, 112.6, 96.1, 74.6,
21.2, 20.9, À4.0; IR (neat) 1740 cmÀ1; HRMS (ESI+) (m/z) calcd for C8H17OSi
[M+HÀCH3CO2H]+ 157.1049, found 157.1052. These data suggest that the
peaks occurring at 6.2 and 6.4 min are diastereomers of 15. In addition the
structure of acetal 15 was consistent with HMQC, HMBC, TOCSY, and COSY
data acquired on the mixture. Independent synthesis of 15 (see Section 4.9)
afforded material that was spectroscopically similar to that formed during the
kinetic resolution. In addition, a GC of the independently synthesized material
also gave peaks at 2.6, 6.2, and 6.4 min, albeit in a different ratio (1:59:40).
17. Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai, Y. M.; Szczepanski, S. W. J. Org.
Chem. 1985, 50, 5393–5396.
Acknowledgments
We thank the NIH (HL-58114), NSF (CHE-9984644), and the
Astellas USA Foundation for their generous support.
References
1. (a) Onyeozili, E. N.; Maleczka, R. E. Tetrahedron Lett. 2006, 47, 6565–6568; (b)
Onyeozili, E. N.; Maleczka, R. E. Chem. Commun. 2006, 2466–2468.
2. Buynak, J. D.; Strickland, J. B.; Lamb, G. W.; Khasnis, D.; Modi, S.; Williams, D.;
Zhang, H. M. J. Org. Chem. 1991, 56, 7076–7083.
3. Arai, N.; Suzuki, K.; Sugizaki, S.; Sorimachi, H.; Ohkuma, T. Angew. Chem., Int. Ed.
2008, 47, 1770–1773.
4. Takeda, K.; Ohnishi, Y.; Koizumi, T. Org. Lett. 1999, 1, 237–239.
5. Lou, W. Y.; Zong, M. H.; Smith, T. J. Green Chem. 2006, 8, 147–155.
6. Lou, W. Y.; Zong, M. H. Chirality 2006, 18, 814–821.
7. (a) Wu, H.; Zong, M. H.; Wang, J. F.; Luo, D. H.; Lou, W. Y. Chin. J. Chem. Eng.
2004, 12, 421–424; (b) Fukui, T.; Zong, M. H.; Kawamoto, T.; Tanaka, A. Appl.
Microbiol. Biotechnol. 1992, 38, 209–213.
18. (a) Marsden, S. P.; McElhinney, A. D. Beilstein J. Org. Chem. 2008, 4; (b) Leonard,
N. M.; Woerpel, K. A. J. Org. Chem. 2009, 74, 6915–6923.
19. Scheller, M. E.; Frei, B. Helv. Chim. Acta 1985, 68, 44–52.
20. Takeda, K.; Ohnishi, Y.; Koizumi, T. Org. Lett. 1999, 1, 237–240.
21. Kamimura, A.; Kaneko, Y.; Ohta, A.; Matsuura, K.; Fujimoto, Y.; Kakehi, A.;
Kanemasa, S. Tetrahedron 2002, 58, 9613–9620.
22. Panek, J. S.; Cirillo, P. F. J. Am. Chem. Soc. 1990, 112, 4873–4878.
23. Huckins, J. R.; Rychnovsky, S. D. J. Org. Chem. 2003, 68, 10135–10145.
24. Barrett, A. G. M.; Hill, J. M.; Wallace, E. M. J. Org. Chem. 1992, 57, 386–389.
25. Linderman, R. J.; Ghannam, A. J. Am. Chem. Soc. 1990, 112, 2392–2398.
26. Linderman, R. J.; Suhr, Y. J. Org. Chem. 1988, 53, 1569–1572.
8. Uejima, A.; Fukui, T.; Fukusaki, E.; Omata, T.; Kawamoto, T.; Sonomoto, K.;
Tanaka, A. Appl. Microbiol. Biotechnol. 1993, 38, 482–486.
9. Guintchin, B. K.; Bienz, S. Organometallics 2004, 23, 4944–4951.
10. Panek, J. S.; Sparks, M. A. Tetrahedron: Asymmetry 1990, 1, 801–816.
11. (a) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129–6139; (b)
Marshall, J. A.; Chobanian, H. R.; Yanik, M. M. Org. Lett. 2001, 3, 3369–3372.
12. The stereochemistry of (R)-1 and (S)-10 was established by method of Trost
using an O-methyl mandelate ester. See: Trost, B. M.; Belletire, J. L.; Godleski,
S.; Mcdougal, P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.;
Varga, S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370–2374.
27. Cossrow, J.; Rychnovsky, S. D. Org. Lett. 2002, 4, 147–150.
28. Lorsbach, B. A.; Prock, A.; Giering, W. P. Organometallics 1995, 14, 1694–1699.
29. Durham, T. B.; Blanchard, N.; Savall, B. M.; Powell, N. A.; Roush, W. R. J. Am.
Chem. Soc. 2004, 126, 9307–9317.
30. Woerpel (Ref. 18b) described the preparation of (S)-3 by reduction of 1-
(dimethylphenylsilyl)-2-propen-1-one with (+)-DIP-Cl, while Marsden (Ref.
18a) reported the preparation of (R)-3 using (À)-DIP-Cl. Curiously, negative
[a] values were reported for both the (R) and (S) enantiomers. To clarify the
D
13. Zong (Ref. 6) also reported a Novozym 435 resolution of 1-TMS-ethanol in ionic
liquids and organic solvents and report %ees for the ‘remaining substrate’,
however, the absolute configuration of the unreacted alcohol when organic
solvents were employed is not explicitly stated. Since the solvent can affect the
absolute course of a kinetic resolution (see (a) Costa, V. E. U.; de Amorim, H. L.
N. Quim. Nova 1999, 22, 863–873 and (b) Singh, M.; Singh, R. S.; Banerjee, U. C.
J. Mol. Catal. B: Enzym. 2009, 56, 294–299), we are uncertain that our results are
uniformly opposite to those obtained with 1-TMS-ethanol.
sign of the [
hands, (R)-3 gave a negative [
HPLC comparison of our enzymatically generated material with both reduction
products following the conditions described in Ref. 18b confirmed the absolute
configurations assigned in Refs. 18a,b.
a] value, we repeated the previously reported reductions. In our
D
a
] and (S)-3 gave a positive [a]D. Importantly,
D
31. In some runs, (S)-1 was formed in greater than 90%ee, however, over 5 runs an
average of 89%ee was observed.
32. Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191–198.